脐带血 DNA 甲基化的 DNMT3A 介导了宫内砷暴露与出生结局之间的关联：来自孟加拉国前瞻性出生队列的结果。
Cord blood DNA methylation of DNMT3A mediates the association between in utero arsenic exposure and birth outcomes: Results from a prospective birth cohort in Bangladesh.
机构信息
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 W. 168th St., New York, NY, 10032, USA.
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, 2121 Berkeley Way, Room 5302, Berkeley, CA, 94720, USA.
出版信息
Environ Res. 2020 Apr;183:109134. doi: 10.1016/j.envres.2020.109134. Epub 2020 Jan 13.
BACKGROUND
Fetal epigenetic programming plays a critical role in development. DNA methyltransferase 3 alpha (DNMT3A), which is involved in de novo DNA methylation (DNAm), is a prime candidate gene as a mediator between prenatal exposures and birth outcomes. We evaluated the relationships between in utero arsenic (As) exposure, birth outcomes, and DNMT3A DNAm.
METHODS
In a prospective Bangladeshi birth cohort, cord blood DNAm of three DNMT3A CpGs was measured using bisulfite pyrosequencing. Maternal toenail As concentrations at birth were measured to estimate in utero exposure. Among vaginal births (N = 413), structural equation models (SEMs) were used to evaluate relationships between DNMT3A methylation, log (toenail As), birth weight, and gestational age.
RESULTS
In an adjusted SEM including birth weight and gestational age, maternal toenail As levels were associated with DNMT3A DNAm (B = 0.40; 95% CI: 0.15, 0.66) and gestational age (B = -0.19 weeks; 95% CI: 0.36, -0.03). DNMT3A DNAm was associated with gestational age (B = -0.10 weeks; 95% CI: 0.16, -0.04) and birth weight (B = -11.0 g; 95% CI: 21.5, 0.4). There was an indirect effect of As on gestational age mediated through DNMT3A DNAm (B = -0.04; 95% CI: 0.08, -0.01), and there were indirect effects of maternal toenail As levels on birth weight through pathways including gestational age (B = -14.4 g; 95% CI: 29.2, -1.9), DNMT3A DNAm and gestational age (B = -3.1 g; 95% CI: 6.6, -0.8), and maternal weight gain and gestational age (B = -5.1 g; 95% CI: 9.6, -1.5). The total effect of a doubling in maternal toenail As concentration is a decrease in gestational age of 2.1 days (95% CI: 0.9, 3.3) and a decrease in birth weight of 29 g (95% CI: 14, 46).
CONCLUSIONS
DNMT3A plays a critical role in fetal epigenetic programming. In utero arsenic exposure was associated with greater methylation of CpGs in DNMT3A which partially mediated associations between prenatal As exposure and birth outcomes. Additional studies are needed to verify this finding.
背景
胎儿表观遗传编程在发育过程中起着关键作用。涉及从头 DNA 甲基化（DNAm）的 DNA 甲基转移酶 3α（DNMT3A）是产前暴露与出生结局之间的中介的候选基因。我们评估了宫内砷（As）暴露、出生结局和 DNMT3A DNAm 之间的关系。
方法
在一项前瞻性的孟加拉国出生队列中，使用亚硫酸氢盐焦磷酸测序法测量脐带血中三个 DNMT3A CpG 的 DNAm。在出生时测量母亲的脚趾甲 As 浓度以估计宫内暴露。在阴道分娩者（N=413）中，使用结构方程模型（SEM）评估 DNMT3A 甲基化、log（脚趾甲 As）、出生体重和胎龄之间的关系。
结果
在包含出生体重和胎龄的调整后的 SEM 中，母亲脚趾甲 As 水平与 DNMT3A DNAm（B=0.40；95%CI：0.15，0.66）和胎龄（B=-0.19 周；95%CI：0.36，-0.03）相关。DNMT3A DNAm 与胎龄（B=-0.10 周；95%CI：0.16，-0.04）和出生体重（B=-11.0g；95%CI：21.5，0.4）相关。As 通过 DNMT3A DNAm 对胎龄的间接影响具有介导作用（B=-0.04；95%CI：0.08，-0.01），母亲脚趾甲 As 水平对出生体重的间接影响通过包括胎龄（B=-14.4g；95%CI：29.2，-1.9）、DNMT3A DNAm 和胎龄（B=-3.1g；95%CI：6.6，-0.8）以及母亲体重增加和胎龄（B=-5.1g；95%CI：9.6，-1.5）等途径发生。母亲脚趾甲 As 浓度翻倍的总效应是胎龄减少 2.1 天（95%CI：0.9，3.3）和出生体重减少 29g（95%CI：14，46）。
结论
DNMT3A 在胎儿表观遗传编程中起着关键作用。宫内砷暴露与 DNMT3A 中 CpG 的更高甲基化有关，这部分解释了产前 As 暴露与出生结局之间的关系。需要进一步的研究来验证这一发现。
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